Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats.
Chronic treatment of saline-drinking stroke-prone spontaneously hypertensive rats (SHRSP) with agents that interfere with the formation or actions of angiotensin II (Ang II) prevents the development of stroke and renal vascular damage. Ang II, in addition to its direct vascular effects, stimulates the synthesis and release of aldosterone. To assess the role of aldosterone in the development of pathologic changes in these rats, we implanted time-release pellets containing 200 mg of the mineralocorticoid receptor antagonist, spironolactone, into 14 SHRSP at 7.5 weeks of age. Eight SHRSP littermates received placebo pellets. Over the period of study (3 to 4 weeks), systolic blood pressure (SBP) was not different between the groups. Spironolactone did not enhance water and electrolyte excretion. All placebo-treated SHRSP developed marked proteinuria (150+/-6 mg/d) whereas in spironolactone-treated SHRSP, urinary protein excretion (UPE) averaged 39+/-9 mg/d (P<.0001). In a second study to assess effects on survival, 6 SHRSP received spironolactone (10 mg/kg/d) and 6 received vehicle. All but one of the control rats displayed signs of stroke and died by 16 weeks of age, while the spironolactone-treated SHRSP remained asymptomatic through 19 weeks of age (P<.03). At 16 weeks of age, spironolactone-treated SHRSP were severely hypertensive (247+/-3 mm Hg), yet UPE remained at baseline levels. In contrast, preterminal UPE averaged 136+/-13 mg/d in control rats (P<.0001). In both studies, histopathologic examination revealed a marked protective effect of spironolactone against the development of malignant nephrosclerotic and cerebrovascular lesions. These observations indicate a vascular and end organ protective effect of spironolactone in the absence of lowered blood pressure in saline-drinking SHRSP and are consistent with a major role for mineralocorticoids as hormonal mediators of vascular injury.
Rocha
R
R
Department of Pharmacology, New York Medical College, Valhalla 10595, USA.
Chander
P N
PN
Khanna
K
K
Zuckerman
A
A
Stier
C T
CT
D000375:Aging / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002561:Cerebrovascular Disorders / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D003692:Delayed-Action Preparations; D004231:Diuresis / Q000187:drug effects; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D011188:Potassium / Q000652:urine; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011918:Rats, Inbred SHR; D012964:Sodium / Q000652:urine; D012982:Sodium, Dietary; D013148:Spironolactone / Q000008:administration & dosage / Q000627:therapeutic use*; D015996:Survival Rate; D013599:Systole / Q000187:drug effects
D003692:Delayed-Action Preparations; D000451:Mineralocorticoid Receptor Antagonists; D012982:Sodium, Dietary; D013148:Spironolactone; D012964:Sodium; D011188:Potassium